Insulin Resistance at the Crossroad of Alzheimer Disease Pathology: A Review

Abstract

Insulin plays a major neuroprotective and trophic function for cerebral cell population, thus countering apoptosis, beta-amyloid toxicity, and oxidative stress; favoring neuronal survival; and enhancing memory and learning processes. Insulin resistance and impaired cerebral glucose metabolism are invariantly reported in Alzheimer's disease (AD) and other neurodegenerative processes. AD is a fatal neurodegenerative disorder in which progressive glucose hypometabolism parallels to cognitive impairment. Although AD may appear and progress in virtue of multifactorial nosogenic ingredients, multiple interperpetuative and interconnected vicious circles appear to drive disease pathophysiology. The disease is primarily a metabolic/energetic disorder in which amyloid accumulation may appear as a by-product of more proximal events, especially in the late-onset form. As a bridge between AD and type 2 diabetes, activation of c-Jun N-terminal kinase (JNK) pathway with the ensued serine phosphorylation of the insulin response substrate (IRS)-1/2 may be at the crossroads of insulin resistance and its subsequent dysmetabolic consequences. Central insulin axis bankruptcy translates in neuronal vulnerability and demise. As a link in the chain of pathogenic vicious circles, mitochondrial dysfunction, oxidative stress, and peripheral/central immune-inflammation are increasingly advocated as major pathology drivers. Pharmacological interventions addressed to preserve insulin axis physiology, mitochondrial biogenesis-integral functionality, and mitophagy of diseased organelles may attenuate the adjacent spillover of free radicals that further perpetuate mitochondrial damages and catalyze inflammation. Central and/or peripheral inflammation may account for a local flood of proinflammatory cytokines that along with astrogliosis amplify insulin resistance, mitochondrial dysfunction, and oxidative stress. All these elements are endogenous stressor, pro-senescent factors that contribute to JNK activation. Taken together, these evidences incite to identify novel multi-mechanistic approaches to succeed in ameliorating this pandemic affliction.

Keywords: Alzheimer's disease; central insuline resistance; neurodegeneration; neurofibrillary tangles; β-amyloid plaques.

Figure 1

Putative mechanistic model of insulin resistance via c-Jun N-terminal kinase (JNK) activation. This simplified putative model describes JNK activation pathway as a phosphorylation target of a variety of extracellular stimuli, e.g., proinflammatory cytokines as well as intracellular stimuli, oxidative stress, and oxidized mtDNA. Upon activation, phosphorylated JNK promotes direct serine phosphorylation of insulin receptor substrate protein IRS1, thus causing a defective IRS1 tyrosine phosphorylation and reduced phosphatidylinositide 3 kinase (PI3K) and AKT signaling in response to insulin receptor activation. Phosphorylation of serine residues inhibits the interaction of IRS1 with the insulin receptor, thereby blocking the response to insulin. Being applicable this model for neuronal IR would lead to disastrous consequences for most of the cellular stirpes within the brain. JNK activation by ROS-free radicals, Aβ, and hyperphosphorylated Tau promotes the transcriptional expression of proinflammatory cytokines, which in turn may enhance the production of ROS, the mitochondrial dysfunction, and the accumulation of neurotoxic Aβ+p-Tau, which ultimately enhance IR. Similarly, RAGE activates the transcription of proinflammatory products. A putative vicious circle would presuppose that ROS spillover within the mitochondrial environment amplifies inflammation, impairs, and damages OXPHOS enzymes and provoke mtDNA damages/mutations. These events ultimately synergize and amplify IR and neuronal energetic collapse, leading to the organelle fragmentation. Accordingly, the pool of dysfunctional and fragmented mitochondria will induce neuronal demise.

Figure 2

Central neuroinflammation and consequences. Increased levels of peripheral and CNS of proinflammatory mediators support the key role of inflammation in AD pathology. Priming of glial cells to mount a protracted proinflammatory phenotype is a critical event that seems linked to aging, circulating peripheral cytokines, ROS, and neurotoxic amyloid β accumulation. Cross talk between microglia and astrocytes leads to the generation of proinflammatory/neurotoxic astrocytes, which further enhance the production of inflammatory cytokines and chemokines leading to a detrimental gliosis and astrocytosis in which, for instance, central IR and neurotoxic β amyloid accumulation are intensified. Under these conditions, mitochondrial function is further impaired, and consequently, free radicals are over-produced. Dysfunctional mitochondrial clearance is impaired. The central proinflammatory environment accounts for the amplification of this series of interrelated events eventually leading to progressive energetic collapse and neuronal and synapsis loss. The inflammatory cascade may become intensified when glial cells are further activated by the presence of released DAMP ligands, for instance, oxidized mtDNA, neuronal sequestered antigens, and accumulated β amyloid. In general, the disease is perpetuated by the interconnection of different pathogenic vicious circles, which amplify each to another.

Figure 3

Alzheimer's disease (AD)-driven primary mitochondrial dysfunction. Although it is still debated “who drives who” along the course of molecular events leading to clinical AD, mitochondrial primary dysfunction is a well-founded hypothesis on the pathogenic cascade of AD. Mitochondrial dysfunction means that bioenergetic derangement is broad enough to trigger and run through a series of critical pathogenic ingredients of AD. A primary defect on mitochondrial physiology could arise from damaged mtDNA, deficit or failure of respiratory enzymes, alterations of oxygen uptake and handling, erroneous or insufficient tagging for a proper organelle purge, etc. The onset of an abnormal mitochondrial function irrevocably leads to neuronal death.

Figure 4

Putative Alzheimer's disease (AD) pathogenic integrative mechanism. Inflammation (either peripheral or central), IR, mitochondrial functional impairment, and the excessive production of ROS with the ensued oxidative damage are concatenated and mutually cooperate as pathogenic drivers. It is likely that one of these four ingredients can consistently drive to others so that a hierarchy of events may turn irrelevant. Inflammation breaches the BBB with the downstream consequences, elicits a neurotoxic environment, and triggers glial and astrocyte activation with further cytokine spillover. Oxidative stress may be an inflammation by-product that in turn amplifies inflammation. Concurrently, free radicals may turn on inflammatory pathways. Moreover, proinflammatory cytokines trigger IR by imposing a loss-of-function pattern of phosphorylation in insulin receptor substrate 1. Importantly, obstruction of cerebral insulin physiology translates neuronal cell vulnerability to inflammation, mitochondrial impairment, and oxidative stress and may be an amplifying factor to each of these nosogenic links. Furthermore, the functional collapse of cerebral insulin leads to increase of β amyloid accumulation, neurotoxicity, and ultimately neuronal demise. Impaired mitochondrial function either by an acquired or inherited defect or via β amyloid accumulation may turn sufficient to dismantle cerebral cell homeostasis.